Zidesamtinib efficacy and safety in patients with advanced <i>ROS1</i> -positive solid tumors other than NSCLC in the ARROS-1 study.

Abstract

3108 Background: ROS1 fusions are oncogenic drivers in various cancers. Multiple ROS1 tyrosine kinase inhibitors (TKIs) are available for ROS1 + non-small cell lung cancer (NSCLC); however, there are limited data on the activity of these agents in patients with other ROS1 + tumors. In patients with advanced ROS1 + NSCLC (TKI pretreated and TKI-naïve), zidesamtinib has demonstrated encouraging clinical activity, including in patients with CNS disease and/or ROS1 G2032R mutation, and a safety profile consistent with its highly ROS1-selective, TRK-sparing design. Here we report the first data on the activity of zidesamtinib in patients with other ROS1 + solid tumors. Methods: The global Phase 1/2 ARROS-1 study (NCT05118789) includes a cohort of patients with advanced/metastatic ROS1 + solid tumors other than NSCLC, whose disease has progressed on any prior therapy. Key endpoints are objective response rate (ORR, RECIST v1.1 by BICR), duration of response (DOR), and safety. Data cut: 22 September 2025. Results: 15 efficacy-evaluable patients with ROS1 + solid tumors (10 non-NSCLC tumor types) received zidesamtinib. Patients received a median of 2 prior anticancer therapies (range 1-6): 60% were ROS1 TKI-naïve, 40% were ROS1 TKI pre-treated (range 1-2), 73% had prior chemotherapy (range 1-4). ORR was 40% (6/15, including 1 PR pending confirmation), with no disease progression by BICR among responders (DOR range 3.9+ – 22.8+ months). Responses were observed across multiple tumor types, including cholangiocarcinoma, colorectal, gastric, inflammatory myofibroblastic tumor, ovarian, and pancreatic. 2 ROS1 TKI pre-treated patients had ROS1 resistance mutations (G2032R and F2004I/F2004V) at baseline and both achieved a PR (1 pending confirmation). Treatment-related adverse events (TRAEs) in ≥15% of patients were increased alanine aminotransferase, increased blood creatine phosphokinase, and dysgeusia (n=3 patients each). No patients discontinued due to TRAEs; 1 pt dose-reduced due to TRAE. Conclusions: Zidesamtinib demonstrated encouraging activity in patients with diverse ROS1 + solid tumors, including those refractory to standard-of-care therapies. Safety was consistent with its ROS1-selective, TRK-sparing design. Enrollment is ongoing. Clinical trial information: NCT05118789 .